Other cycloisomerization

In addition to the reactions discussed above, there are still other alkyne reactions carried out in aqueous media. Examples include the Pseudomonas cepacia lipase-catalyzed hydrolysis of propargylic acetate in an acetone-water solvent system,137 the ruthenium-catalyzed cycloisomerization-oxidation of propargyl alcohols in DMF-water,138 an intramolecular allylindination of terminal alkyne in THF-water,139 and alkyne polymerization catalyzed by late-transition metals.140... 

A new synthetic route for functionalized polyhydroxyalkyl-pyrimidines starting from unprotected aldoses and based on montmorillonite K-10 catalysis and solvent-free microwave irradiation conditions, has been reported by Yadav et al,m Thus, reaction of D-glucose and D-xylose with semicarbazide or thiosemicarbazide (186) in the presence of montmorillonite K-10, under microwave irradiation, proceeded via domino cycloisomerization, dehydrazination, and dehydration of the intermediate semi- or thiosemicarbazones (187) to afford l,3-oxazin-2-ones or l,3-oxazine-2-thiones (188) in one single step and in yields between 79% and 85% (Scheme 34). Other mineral catalysts tested, such as silica gel and basic alumina, were far less effective for this transformation and only silica gel was active at all, giving low yields (15-28%) of compounds 188a-d. The l,3-oxazin-2-ones(thiones) thus synthesized were subsequently converted into the target pyrimidines by reaction with aromatic... 

Trost and others have extensively studied the ruthenium-catalyzed intermolecular Alder-ene reaction (see Section 10.12.3) however, conditions developed for the intermolecular coupling of alkenes and alkynes failed to lead to intramolecular cycloisomerization due the sensitivity of the [CpRu(cod)Cl] catalyst system to substitution patterns on the alkene.51 Trost and Toste instead found success using cationic [CpRu(MeCN)3]PF6 41. In contrast to the analogous palladium conditions, this catalyst gives exclusively 1,4-diene cycloisomerization products. The absence of 1,3-dienes supports the suggestion that the ruthenium-catalyzed cycloisomerization of enynes proceeds through a ruthenacycle intermediate (Scheme 11). 

Zhang54 published the first and only account of a non-asymmetric rhodium-catalyzed Alder-ene cycloisomerization of 1,6-enynes.55 The conditions developed by Zhang and co-workers are advantageous in that, similar to the ruthenium conditions developed by Trost, selectivity for 1,4-diene products is exhibited. The rhodium conditions are dissimilar from many other transition metal conditions in that only (Z)-olefins give cycloisomerization products. 

Using a protocol for tandem carbonylation and cycloisomerization, Mandai et al.83 were able to synthesize cyclopentene and cyclohexene derivatives in high yield, including fused and 5/>/>0-bicycles (Scheme 25). The cyclohexene Alder-ene products were not isolable methanol addition across the exocyclic double bond (in MeOH/ toluene solvent) and olefin migration (in BuOH/toluene solvent) were observed. The mechanism of methanol addition under the mild reaction conditions is unknown. In contrast to many of the other Pd conditions developed for the Alder-ene reaction, Mandai found phosphine ligands essential additionally, bidentate ligands were more effective than triphenylphosphine. 

For selected examples of the cycloisomerization of 1,6-enynes catalyzed by metals other than palladium, see (a) Titanium ... 

The Diels-Alder reaction outlined above is a typical example of the utilization of axially chiral allenes, accessible through 1,6-addition or other methods, to generate selectively new stereogenic centers. This transfer of chirality is also possible via in-termolecular Diels-Alder reactions of vinylallenes [57], aldol reactions of allenyl eno-lates [19f] and Ireland-Claisen rearrangements of silyl allenylketene acetals [58]. Furthermore, it has been utilized recently in the diastereoselective oxidation of titanium allenyl enolates (formed by deprotonation of /3-allenecarboxylates of type 65 and transmetalation with titanocene dichloride) with dimethyl dioxirane (DMDO) [25, 59] and in subsequent acid- or gold-catalyzed cycloisomerization reactions of a-hydroxyallenes into 2,5-dihydrofurans (cf. Chapter 15) [25, 59, 60],... 

Hashmi et al. investigated a number of different transition metals for their ability to catalyze reactions of terminal allenyl ketones of type 96. Whereas with Cu(I) [57, 58] the cycloisomerization known from Rh(I) and Ag(I) was observed (in fact the first observation that copper is also active for cycloisomerizations of allenes), with different sources of Pd(II) the dimer 97 was observed (Scheme 15.25). Under optimized conditions, 97 was the major product. Numerous substituents are tolerated, among them even groups that are known to react also in palladium-catalyzed reactions. Examples of these groups are aryl halides (including iodides ), terminal alkynes, 1,6-diynes, 1,6-enynes and other allenes such as allenylcarbinols. This che-moselectivity might be explained by the mild reaction conditions. 

In other Pd(II)-catalyzed reactions, combining a cyclization with a coupling reaction, the furans which stem from a simple cycloisomerization reaction without coupling are often observed as side-products, occasionally in significant yield. Several examples have been reported by Ma and co-workers [74, 75],... 

Marshall and co-workers used the silver-catalyzed version of this cycloisomerization as the final step in the synthesis of (-)-kallolide B from precursor 115 (Scheme 15.33) [51, 54]. Again, the reaction is stereospecific, as has also been demonstrated in the synthesis of kallolide A [55] and other examples [77]. 

Other applications include the synthesis of (-)-deoxypukalide by Marshall and Van Devender, where an Ag(I)-catalyzed cycloisomerization of 118 to 119 again is very late in the sequence (Scheme 15.35) [79], and the synthesis of rubifolide [53], Furthermore, studies on the synthesis of pseudopterane analogues have been conducted [80],... 

In 1979, Claesson et al. observed the formation of the dihydropyrrole 125 and the pyrrole 126 when trying to purify the amine 124 by GLC [85]. They suspected that an initial cycloisomerization first leads to 125 and a subsequent dehydrogenation then delivers 126. Guided by other intramolecular nucleophilic additions to alkynes that are catalyzed by AgBF4, they discovered that this catalyst efficiently allowed the transformation of 124 to 125 (Scheme 15.38). Reissig et al. found that with enantio-merically pure substrates of that kind a cyclization without racemization is possible with Ag(I) catalysts [86],... 

Other catalytic reactions involving a transition-metal allenylidene complex, as catalyst precursor or intermediate, include (1) the dehydrogenative dimerization of tributyltin hydride [116], (2) the controlled atom-transfer radical polymerization of vinyl monomers [144], (3) the selective transetherification of linear and cyclic vinyl ethers under non acidic conditions [353], (4) the cycloisomerization of (V2V-dia-llyltosylamide into 3-methyl-4-methylene-(V-tosylpyrrolidine [354, 355], and (5) the reduction of protons from HBF4 into dihydrogen [238]. 

Brummond [28] was the first to illustrate that cross-conjugated trienes could be obtained via an allenic Alder-ene reaction catalyzed by [Rh(CO)2Cl]2 (Eq. 14). Selective formation of the cross-conjugated triene was enabled by a selective cycloisomerization reaction occurring with the distal double bond of the aUene. Typically directing groups on the allene, differential substitution of the aUene termini, or intramolecularization are required for constitutional group selectivity. However, rhodium(f), unlike other transition metals examined, facihtated selective cyclization with the distal double bond of the allene in nearly aU the cases examined. 

Based on the formal analogy between the intermolecular hydrovinylation and the intramolecular cycloisomerization process, we have chosen catalysts with proven potential for the first reaction type [48, 51] as the starting point of our study. The results are summarized in Table 2.1.5.7 [64]. Despite its excellent performance in the hydrovinylation of styrene [51], the [ Ni(allyl) Br 2]/(Ra, Sc, Sc)-26/NaBARF system led to disappointingly low conversions and selectivities in the cycloisomerization of 27a (entry 1). Similarly, the [ Ni(allyl)Cl 2]/(Ra,Rc)-4cel/Na-BARF system is not effective for the cycloisomerization of 27a (entry 2) even though it is able to promote the hydrovinylation. The other diastereomer, (R ,Sc)-4cel, however, which forms an active nickel catalyst for styrene oligomerization... 

On the other hand, Takacs and coworkers added organometallic reducing agents to the reaction mixture and promoted the formation of low-valent iron(O) bipyridine complexes. The mechanism of the low-valent iron-catalyzed Alder-ene reaction involves coordination of the two starting materials within the ligand sphere of the iron, which makes the Woodward-Hoffmann rules for such reactions obsolete [11]. Thereby, the scope of the reactions was broadened so that alkenes and 1,3-dienes could also be used as educts in a formal [4 + 4]-cycloisomerization (Scheme 9.3) [12]. Intriguingly, the diastereoselectivity of the cydopentane products can be influenced by either the application of the 2Z-isomer 3 or the 2 E-isomer 4. Especially the E-isomers 4 gave almost exclusive cis selectivity [13]. 

Terminal alkynals (113) of appropriate length (n = 1, 2) and substitution [X = C(C02-Me)2, C(CH2OR)2, NTs, and others] have been cyclized with decarbonylation to cycloalkenes (114), using a ruthenium(I) catalyst.348 In some cases, cycloisomerization to give conjugated aldehyde occurred. Both processes are believed to involve catalytic ruthenium vinylidenes. 

Murai et al. showed that the cycloisomerization of enynes catalyzed by PtCl2 has several feasible pathways (1) to 1,3-dienes via a formal metathesis, (2) to a 1,4-diene if the enyne substrates contains an allylsilane or stannane, (3) to a homo-allylic ether if it the reaction is performed in an alcoholic medium, or (4) to bicycle[4.1.0]heptene derivatives (Scheme 4) [26]. Further studies conducted by other groups have indicated the cyclization might proceed via a cationic mechanism triggered by coordination of Pt(II) with the alkyne moiety [27, 28]. Very recently, Oi and coworkers also observed a formal metathesis reaction mediated by a cationic Pt complex [29]. 

On comparison with other metallic species, we are able to detect areas where efforts are still needed, such as the cycloisomerization of simple nonactivated ene-yne systems, as well as C-H bond activation. 

Furthermore, the choice of enyne substrates can lead to cyclized products that contain other functionalities than dienes. Very recently, Muller and Kressierer [148] have shown that yne allyl alcohols 200 can be rapidly cyclo-isomerized by a Pd2dba3-W-acetyl phenyl alanine catalyst system to furnish heterocyclic enals 202 in excellent yields (Scheme 82). The intermediate product of the enyne cycloisomerization in this case is the enol 201, which rapidly tautomerizes to the aldehyde 202. 

Abstract This review gives an insight into the growing field of transition metal-catalyzed cascades. More particularly, we have focused on the construction of complex molecules from acyclic precursors. Several approaches have been devised. We have not covered palladium-mediated cyclizations, multiple Heck reactions, or ruthenium-catalyzed metathesis reactions because they are discussed in others chapters of this book. This manuscript is composed of two main parts. In the first part, we emphasize cascade sequences involving cycloaddition, cycloisomerization, or ene-type reactions. Most of these reaction sequences involve a transition metal-catalyzed step that is either followed by another reaction promoted by the same catalyst or by a purely thermal reaction. A simple change in the temperature of the reaction mixture is often the only technical requirement to go from one step to another. The second part covers the cascades relying on transition metalo carbenoid intermediates, which have recently undergone tremendous... 

The metal-catalyzed conversion of 2,3-allenoates to A -butenolides has proven to be superior to the acid-catalyzed cyclization of the corresponding carboxylic acids. The reaction of the esters can be effected by Au(m) catalysts in improved yields <2005TL7431>, and furan-2(5//)-ones functionalized in the 4-position can be prepared by iodo- or seleno-lactonization in moderate to good yields (Scheme 33) <2006T4444, 2005EJO3942>. The cycloisomerization of optically active 2,3-allE itoic acids, on the other hand, can proceed with complete conservation of stereochemical information when copper(i) chloride is used as a catalyst <2006S3711>. 

Based on these studies and choosing to focus on Ru for practical considerations such as cost, we envisioned a possible catalytic cycle shown in Scheme 1.1, wherein an oa-alkynyl alcohol 1 would cycloisomerize to the dihydropyran. Although McDonald s group has pioneered the use of molybdenum- and tungsten-mediated processes, several issues related to chemoselectivity and the common need for stoichiometric amounts make the development of other catalysts for such processes desirable [8]. Using CpRu(PAr3)2Cl-based complexes, less electron-rich arylpho-sphine ligands such as m- or p-fluorophenylphosphines promote such processes (Equation 1.2) [9]. 

In the case of the cyclic substrate 51, the intervention of a C-H insertion pathway reveals itself in terms of the diastereoselectivity, not regioselectivity. Thus, exposure of enyne 51 to the standard Ru catalyst at ambient temperature produced the transfused bicyclo[5.4.0]undecene 52 (Equation 1.60, path a) [55]. If a metallacycle mechanism was operative, coordination of the metal with both the alkene and alkyne must occur to form the cis-fused product. On the other hand, coordination of the Ru with the Lewis basic bridgehead substituent directs it to abstract an allylic C-H on the same face as the substituent, which then leads to the trans-fused product as observed. On the other hand, cycloisomerization using a Pd(0) precatalyst does indeed lead to the Z-fused bicycle (Equation 1.60, path b). 

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